Aromatic-substituted imidazolate

Heterocyclic amines are compounds that contain one or more nitrogen atoms as part of a ring. Saturated heterocyclic amines usually have the same chemistry as their open-chain analogs, but unsaturated heterocycles such as pyrrole, imidazole, pyridine, and pyrimidine are aromatic. All four are unusually stable, and all undergo aromatic substitution on reaction with electrophiles. Pyrrole is nonbasic because its nitrogen lone-pair electrons are part of the aromatic it system. Fused-ring heterocycles such as quinoline, isoquinoline, indole, and purine are also commonly found in biological molecules. 

The imidazole ring is a privileged structure in medicinal chemistry since it is found in the core structure of a wide range of pharmaceutically active compounds efficient methods for the preparation of substituted imidazole libraries are therefore of great interest. Recently, a rapid synthetic route to imidazole-4-carboxylic acids using Wang resin was reported by Henkel (Fig. 17) [64]. An excess aliphatic or aromatic amine was added to the commercially available Wang-resin-bound 3-Ar,M-(dimethylamino)isocyano-acrylate, and the mixture was heated in a sealed vial with microwave irradi-... 

With sUght modifications of these conditions it is possible to prepare mono N-substituted imidazoles (Scheme 5), the reaction working well with aliphatic amines but not with many aromatic amines. The imsymmetrical... 

The O-silylated acyloins such as 1920 c and 1927 are useful synthons for preparation of five-membered aromatic heterocycles such as the substituted imidazole 1925, pyrrole 1926, and furan 1928 [119] (Scheme 12.35). 

Nucleophilic aromatic substitutions 1,3-azoles are more reactive than pyrrole, furan or thiaphene towards nucleophilic attack. Some examples of nucleophilic aromatic substitutions of oxazole, imidazole and thiazoles and their derivatives are given below. In the reaction with imidazole, the presence of a nitro-group in the reactant can activate the reaction because the nitro-group can act as an electron acceptor. 

Substituted imidazole 1-oxides 228 are predicted to be activated toward electrophilic aromatic substitution, nucleophilic aromatic substitution, and metallation as described in Section 1. Nevertheless little information about the reactivity of imidazole 1-oxides in these processes exists. The reason for this lack may be the high polarity of the imidazole 1-oxides, which makes it difficult to find suitable reaction solvents. Another obstacle is that no method for complete drying of imidazole 1-oxides exists and dry starting material is instrumental for successful metallation. Well documented and useful is the reaction of imidazole 1-oxide 228 with alkylation and acylation reagents, their function as 1,3-dipoles in cycloadditions, and their palladium-catalyzed direct arylation. 

Only few imidazole 1-oxides possessing leaving groups like compound 278 are known. Although predicted to be apt to undergo nucleophilic aromatic substitution (see Section 1.4.2) such reactions have not been reported. 

Nucleophilic aromatic substitution of oxazoles, imidazoles, and thiazoles... 

The relationship between the delocalized imidazole anion and imidazole itself is rather like that between an enolate anion and an enol. It will come as no surprise that imidazole tautomerizes rapidly at room temperature in solution. For the parent compound the two tautomers are the same, but with unsymmetrical imidazoles the tautomerism is more interesting. We will explore this question alongside electrophilic aromatic substitution of imidazoles. 

Allied with the chromatography of imidazoles have been methods of estimation of the compounds, particularly those of biological importance, either on the chromatograms or after elution. Most workers have used diazotized aromatic amines as colorimetric reagents,53,277-285 particularly nonsulfonated diazotized aniline derivatives.281-285 Mosebach et aZ.286 initially hydrolyzed. -substituted imidazoles with 10 A hydrochloric acid before separating the compounds by ion-exchange and paper chromatographic techniques prior to estimation. A number of other methods exist for the colori-... 

This may imply that the intermolecular coupling of various aryl halides with other heteroaromatic compounds may proceed. Indeed, it is now known that not only the special heteroaromatic halides but also usual aryl halides can react with a variety of five-membered aromatic heterocycles, including furans, thiophenes, and azole compounds such as M-substituted imidazoles, oxazoles, and thiazoles [133-137]. The arylation of azoles can be carried out using iodobenzoate immobilized on an insoluble polymer support [138]. Related intermolecular reactions of indole [139] and imidazole [140] derivatives have also been reported. 

The purine ring system represents a fusion of the two aromatic heterocycles pyrimidine and imidazole. As a logical consequence, appropriately substituted pyrimidines or imidazoles have been used as precursors followed by a cyclization reaction. The purine heterocycle can also be formed from simple acyclic precursors. The most widely used method to synthesize purine is the addition of an imidazole ring to a functionalized pyrimidine moiety (Traube synthesis). The alternative route for the formation of the purine system by the annulation of the pyrimidine ring to a substituted imidazole relates back to a method of Sarasin and Wegmann, and these synthetic protocols principally follow the biosynthetic pathway of purine synthesis. 

Scheme 2.3.3). The approach has been used to make imidazoles (11) with dimethylamino groups in the 4- and/or 2-positions. Such compounds are not well known (they are inclined to be sensitive to the elfects of air and moisture, and their behaviour in electrophilic aromatic substitution reactions parallels that of i (A(-dimethylaniline [8]), and the method is of value for that reason alone. Its wider application to imidazole synthesis seems unlikely. 

N-arylimidazoles, important compounds in medicinal research, have been synthesized by nucleophilic aromatic substitution and Ulmann-type coupling. Aromatic substitution is, however, limited by the need for substrates activated by electron-withdrawing groups. The arylation of diazoles and triazoles, e.g. imidazole, by p-tolyllead triacetate compares very favorably with the Ullmann and related methods in that the conditions employed are much milder and the yields are usually excellent and reproducible (Scheme 13.43) [64]. 

The Chichibabin reaction with imidazoles has been the subject of extensive study in the U.S.S.R. (82CHE1221). Criteria for successful amination require that the imidazole ring be condensed with an aromatic system at the 4-and 5-positions, and that the pyrrole nitrogen be substituted (Scheme 72) (73CHE88). Another requirement is that the heterocycle must have a pK, of at least 4.3 for heterogeneous aminations. The parent compound, imidazole, substituted in the 1-position, does not undergo the Chichibabin reaction. Even substituted imidazoles such as phenanthro[9,10-d] imidazole (204) do not aminate (73CHE88). 

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